Heart and coronary disease is one of the leading causes of mortality in the United States and other parts of the world. When partial or complete closure of a coronary artery occurs a balloon angioplasty is commonly performed to re-open the artery. In this procedure, a catheter is introduced into the coronary artery by access through a small opening in the patient's femoral artery above the thigh. The tip of the catheter has a cylindrical balloon, which is inflated at the site of the blockage and expands the artery, usually compressing the plaque resulting in a substantial increase in blood flow. However, in many cases the plaque quickly accumulates to reclose the artery. This phenomena is called restenosis. It is generally accepted that the most important contributors to restenosis are elastic recoil of the dilated artery, neointimal proliferation, which leads to the thickening of the vessel wall, and unfavorable vascular remodeling, which causes contraction of the artery. Restenosis, after successful coronary angioplasty, is the major limitation to long-term success of the balloon angioplasty.
Despite numerous trials of pharmacological agents, including anticoagulants, corticosteroids, calcium-channels, fish oil, and others, the frequency of restenosis has not diminished (Pepine, C. J., Hirsgfield, J. W., and Macdonald, R. G., “A Controlled Trial of Corticosteroids to Prevent Restenosis after Coronary Angioplasty,” Circulation, Vol. 81, pp. 1753-1761 (1990); Whitworth, H. B., Roubin G. S., Hollman, J., Meier, B., Leimgruber, P. P., Douglas, J. S., King, S. B., III, and Gruentzig, A. R., “Effect of Nifedipine on Recurrent Stenosis after Percutaneous Transluminal Coronary Angioplasty,” Journal of American College of Cardiology, Vol. 8, pp. 1271-1276 (1986)).
The most common technique currently used for restenosis treatment is placement of stents in arteries after balloon angioplasty. It has been demonstrated that placing stents into arteries after balloon angioplasty successfully addresses remodeling and significantly reduces the restenosis rate (Serruys, P., De Jaegere, P., Kiemeneji, F., Macaya, C., Rutsch, W., Margo, J., Materne, P., Sigwart, U., Colombo, A., Delcan, J., and Morel, M., “A Comparison of Balloon-Expandable-Stent Implantation with Balloon Angioplasty in Patients with Coronary Artery Disease,” The New England Journal of Medicine, Vol. 331, no. 8, pp. 489-495 (1994); Ellis, S. G., Savage, M., and Fischman, D., “Restenosis after Placement of Palmaz-Schatz Stents in Native Coronary Arteries: Initial Results of a Multicenter Experience,” Circulation, Vol. 86, pp. 1836-1844 (1992)). Though use of stents reduces the restenosis rate, at the same time, stents, as foreign objects in the body, can increase cellular proliferation in surrounding tissue and make the neointimal component of restenosis even worse. Furthermore, the majority of, if not all, stents currently available are metallic and thus thrombogenic. This problem can necessitate anticoagulation therapy (Schatz, R., Baim, D., and Leon, M., “Clinical Experience with the Palmaz-Schatz Coronary Stent,” Circulation, Vol. 83, pp. 148-161 (1991)). Anticoagulation therapy can expose the patient to an increases risk of major bleeding and vascular complications (de Jaegere, P., de Feyter, P. J., van der Giessen, W. J., and Serruys, P. W., “Endovascular Stents: Preliminary Clinical Results and Future Developments,” Clinical Cardiology, Vol. 16, pp. 369-378 (1993)). Treatment with lasers does not appear to improve the problem of restenosis (Topol, E. J., Leya, F., and Pinkerton, C. A., “A Comparison of Directional Atherectomy with Coronary Angioplasty in Patients with Coronary Artery Disease,” The New England Journal of Medicine, Vol. 329, pp. 221-227 (1993); Bittl, J., Sanborn, T., Tcheng J. E., Siegel, R, and Ellis, S. G., “Clinical Success, Complications and Restenosis Rates with Excimer Laser Coronary Angioplasty,” American Journal of Cardiology, Vol. 70, pp. 1533-1539 (1992)). It appears that low dose irradiation may inhibit neointimal formation following coronary artery balloon angioplasty. (Waksman, R., Roninson, K. A., Crocker, R., Gravanis, B., Cipolla, G., and King, S., “Endovascular Low Dose radiation Inhibits Neointimal Formation After Coronary Artery Balloon Injury in Swine: A Possible Role for Radiation Therapy in Restenosis Prevention,” Circulation, Vol. 91, pp. 1533-1539 (1995); Weidermann, J. G., Marboe, C., Almos, H., Schwartz, A., and Weinberger, J., “Intracoronary Irradiation Markedly Reduces Neointimal Proliferation After Balloon Angioplasty in Swine,” Journal of American College of Cardiology, Vol. 25, pp. 1451-1456 (1995); Verin, V., Popovski, Y., Urban, P., Belenger, J., Redard, M., Costa, M., Widmer, M., Rouzaud, M., Nouet, P., Grob, E., Schwager, M., Kurtz, J., and Rutishauser, W., “Intra-arterial Beta Irradiation Prevents Neointimal Hyperplasia in a Hypercholesteroliemic Rabbit: Restenosis Model,” Circulation, vol. 92, pp. 2284-2290 (1995); Teirstein, P. S., Massullo, V., Jani, S., Russo, R., Schatz, R., Sirkin, K., Norman, S., and Tripuraneni, P., “Two-Year Follow-Up after Catheter-Based Radiotherapy to Inhibit Coronary Restenosis,” Circulation, Vol. 99, no. 2, pp. 243-247 (1999)). Thus, there is a need for a treatment of restenosis which can reduce the drawbacks associated with current treatments.
There is uncertainty as to the healing mechanism of x-ray irradiated injured vessels. Also, it is not clear what long-term side effects of irradiation therapy there may be. It appears that a safe dosage rate is on the order of 8-30 Gy (1 Gy=1 J/kg), while lower radiation doses appear to be unable to significantly inhibit restenosis (Coursey, B. M., and Nath, R., “Radionuclide Therapy,” Physics Today, pp. 25-30, April (2000).